Cancer is a disease characterized by uncontrolled proliferation, resulting from aberrant signal transduction. The most dangerous forms of cancer are malignant cells which have the ability to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis. Metastatic cells have acquired the ability to break away from the primary tumor, translocate to distant sites through the bloodstream or lymphatic system, and colonize distant and foreign microenvironments.
It is now clear that the Eph molecules are involved in disease states such as cancer. Eph receptors are a unique family of receptor tyrosine kinases (RTK), the largest in the genome, consisting of fourteen receptors, divided into two groups A and B, that interact with eight membrane-bound ephrin ligands (Pasquale, E. B. et al., 2005, Nature Reviews Mol. Cell. Biol., 6: 462-475). Binding of Eph receptors to their ligands induces receptor clustering, activation of kinase activity, and subsequent trans-phosphorylation of the cytoplasmic domains on tyrosine residues, creating docking sites for a number of signaling proteins (Kullander, K. and Klein, R., 2002, Nature Reviews Mol. Cell. Biol., 3: 475-486; Noren, N. K. and Pasquale, E. B., 2004, Cell signal., 16: 655-666).
Overexpression of the EphA2 receptor has been reported in cancers of the ovary, breast, prostate, lung, colon, oesophagus, renal cell, cervix, and melanoma. EphA2 was suggested to be a positive regulator of cell growth and survival in malignant cells (Landen, C. N. et al., 2005, Expert. Opin. Ther. Targets, 9 (6): 1179-1187). A role for EphA2 in cancer has also been described, since EphA2 overexpression alone is sufficient to transform mammary epithelial cells into a malignant phenotype (Zelinski et al., 2001, Cancer Res., 61: 2301-2306), and increases spontaneous metastasis to distant sites (Landen, C. N. et al., 2005, Expert. Opin. Ther. Targets, 9 (6): 1179-1187). Furthermore, increasing evidence suggests that EphA2 is involved in tumor angiogenesis (Ogawa et al., 2000, Oncogene, 19: 6043-6052; Cheng et al. 2002, Mol. Cancer. Res., 1: 2-11; Cheng et al., 2003, Neoplasia, 5 (5): 445-456; Dobrzanski et al., 2004, Cancer Res., 64: 910-919).
Phosphorylation of EphA2 has been shown to be linked to its abundance. Tyrosine phosphorylated EphA2 is rapidly internalized and fated for degradation, whereas unphosphorylated EphA2 demonstrates reduced turnover and therefore accumulates at the cell surface. It is currently thought that this kind of model might contribute to the high frequency of EphA2 overexpression in cancer (Landen, C. N. et al., 2005, Expert. Opin. Ther. Targets, 9 (6): 1179-1187). However, reality may be more complex, since recent data seem to indicate a role for EphA2 kinase-dependent and -independent functions in tumor progression (Fang W. B., 2005, Oncogene, 24: 7859-7868).
Agonistic antibodies have been developed which promote EphA2 tyrosine phosphorylation and internalization, ultimately resulting in inhibition of tumor cell growth (Dodge-Zantek et al., 1999, Cell Growth & Differ., 10: 629-638; WO 01/12172, WO 03/094859, WO 2004/014292, WO 2004/101764, WO 2006/023403, WO 2006/047637, WO 2007/030642).
Application WO 2006/084226 discloses antibodies which neither increase nor decrease EphA2 kinase activity but are capable of impeding tumor cell proliferation. However, there is no indication therein that these antibodies prevent ephrinA1 binding to the receptor and inhibit ephrinA1-induced EphA2 phosphorylation. The use of antagonistic antibodies has been proposed in WO 2004/092343, but no actual antibody was disclosed therein. Antibodies recognizing EphA2 which are genuine antagonists have been described in WO 2008/010101, as well as humanized variants and conjugates thereof. These antibodies and derivatives thereof inhibit EphA2 kinase-dependent tumor cell growth.
Nevertheless, there is still a need for novel and efficacious medicaments which can be used in cancer therapy.